Citations

Abstract Amyloidosis refers to an etiologically heterogeneous group of protein misfolding diseases, pathologically characterized by extracellular amyloid fibrils producing congophillic amorphous deposits in organs and tissues, which may lead to severe organ dysfunction and mortality. Clinical presentations vary and are often nonspecific, depending on what organs or tissues are affected. In systemic amyloidosis, the peripheral nervous system is commonly affected, whereas the skeletal muscles are only rarely involved. Immunoglobulin light chain (AL) amyloidosis and hereditary transthyretin (ATTRv) amyloidosis are the most frequent types of systemic amyloidosis involving the neuromuscular system. Localized amyloidosis can occur in skeletal muscle, so‐called isolated amyloid myopathy. Amyloid neuropathy typically involves small myelinated and unmyelinated sensory and autonomic nerve fibers early in the course of the disease, followed by large myelinated fiber sensory and motor deficits. The relentlessly progressive nature with motor, painful sensory and severe autonomic dysfunction, profound weight loss, and systemic features are distinct characteristics of amyloid neuropathy. Amyloid myopathy presentation differs between systemic amyloidosis and isolated amyloid myopathy. Long‐standing symptoms, distal predominant myopathy, markedly elevated creatine kinase level, and lack of peripheral neuropathy or systemic features are highly suggestive of isolated amyloid myopathy. In ATTR and AL amyloidosis, early treatment correlates with favorable outcomes. Therefore, awareness of these disorders and active screening for amyloidosis in patients with neuropathy or myopathy are crucial in detecting these patients in the everyday practice of neuromuscular medicine. Herein, we review the clinical manifestations of neuromuscular amyloidosis and provide a diagnostic approach to this disorder.

AbstractBackgroundMultiple mononeuropathy is a rare presentation of primary (AL) amyloidosis and nerve biopsy is usually needed for diagnosis. Conventional imaging is useful to identify proximal nerve involvement but may be inadequate. We report a patient with multiple mononeuropathy whose presentation was suggestive of AL amyloid neuropathy and in whom repeated tissue biopsies were negative for amyloid (including two sensory nerves and one muscle).MethodsThe patient underwent magnetic resonance imaging (MRI) and whole body 18F‐florbetapir positron emission tomography (PET)/MRI.ResultsWhole body 18F‐florbetapir PET/MRI revealed abnormal low‐level florbetapir uptake in the right proximal tibial and peroneal nerves, which provided a target for a sciatic bifurcation fascicular nerve biopsy that was diagnostic of AL amyloidosis.Conclusions 18F‐florbetapir PET/MRI imaging is a promising diagnostic tool for patients with suspected peripheral nerve amyloidosis (including multiple mononeuropathy) in whom conventional imaging and nerve and muscle biopsies miss the pathology.

AbstractChronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterized by progressive weakness and sensory loss, often affecting patientsʼ ability to walk and perform activities of daily living independently. With the lack of a diagnostic biomarker, the diagnosis relies on clinical suspicion, clinical findings, and the demonstration of demyelinating changes on electrodiagnostic (EDx) testing and nerve pathology. As a result, patients can often be misdiagnosed with CIDP and unnecessarily treated with immunotherapy. Interpreting the EDx testing and cerebrospinal fluid findings in light of the clinical phenotype, recognizing atypical forms of CIDP, and screening for CIDP mimickers are the mainstays of the approach to patients suspected of having CIDP, and are detailed in this review. We also review the currently available treatment options, including intravenous immunoglobulin (IVIg), corticosteroids (CCS), and plasma exchange (PE), and discuss how to approach treatment‐refractory cases. Finally, we emphasize the need to adopt objective outcome measures to monitor treatment response.

Abstract Objectives: The objective of the study is to distinguish the mechanisms of disease for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN), which we believe to be fundamentally different. However, distinguishing the mechanisms is more difficult when the presentation of CIDP is motor-predominant, focal, or asymmetric. Methods: We describe 3 focal, motor-predominant, representative cases that could be interpreted on clinical and/or electrophysiological grounds as either MMN or focal CIDP, and present pathological findings. Results: We highlight pathological differences in these cases, and provide an argument that CIDP and MMN are distinct entities with different pathophysiological mechanisms—chronic demyelination for CIDP, and an immune-mediated attack on paranodal motor axons for MMN. Conclusions: Based on clinical evaluation, electrophysiology, and nerve biopsy pathology, we can divide the conditions into inflammatory demyelinating neuropathy (focal CIDP) versus chronic axonal neuropathy (MMN). The divergent pathological findings provide further evidence that CIDP and MMN are fundamentally different disorders.

AbstractIntroductionInotersen, an antisense oligonucleotide inhibitor of transthyretin (TTR) protein production, demonstrated significant benefit versus placebo in the modified Neuropathy Impairment Score (NIS) +7 neurophysiologic tests (mNIS+7) in patients with hereditary TTR‐mediated amyloidosis (hATTR) with polyneuropathy. This analysis assessed the mNIS+7 components by anatomic location and the lower limb function (LLF) test.MethodsAdults with hATTR in the NEURO‐TTR trial (NCT01737398) were randomly assigned to receive weekly doses of subcutaneous inotersen 300 mg or placebo for 65 weeks. The mNIS+7 and LLF were assessed at 35 and 66 weeks.ResultsAll major mNIS+7 components (muscle weakness, muscle stretch reflexes, sensation) and the LLF showed significant efficacy in patients receiving inotersen versus placebo; however, NIS‐reflexes (upper limb), touch pressure (upper and lower limbs), and heart rate during deep breathing did not show significant effects.DiscussionThe results of this analysis reinforce the beneficial effect of inotersen on slowing neuropathy progression in patients with hATTR polyneuropathy.

AbstractIntroductionHereditary transthyretin‐mediated amyloidosis (hATTR) manifests as multisystem dysfunction, including progressive polyneuropathy. Inotersen, an antisense oligonucleotide, improved the course of neuropathic impairment in patients with hATTR in the pivotal NEURO‐TTR study (NCT01737398). To determine inotersen's impact on symptoms and patients’ neuropathy experience, we performed a post hoc analysis of the Neuropathy Symptoms and Change (NSC) score.MethodsStage 1 or 2 hATTR patients were randomized to receive weekly subcutaneous inotersen or placebo for 65 weeks. NSC score was assessed at baseline and 35 and 66 weeks.ResultsAt 66 weeks, inotersen‐treated patients had symptom stabilization as compared with worsening in patients receiving placebo, based on total NSC score. There were also improvements in the subdomains of muscle weakness, sensory, pain, and autonomic symptoms, and for various individual items.DiscussionInotersen treatment stabilized neuropathy symptoms, including autonomic symptoms, in patients with hATTR according to NSC score. Thus, the NSC may be an effective measure to assess neuropathy progression and patients’ neuropathy experience in clinical practice.